Advances in recombinant-DNA technology have made introduction of therapeutic genes into somatic cells possible (Anderson W.F., Human gene Therapy. Science 256:808-813,1992; Miller A. D., Human gene therapy comes of age. Nature 357:455-457, 1992). In recent years several clinical trials involving human gene therapy have been accepted by regulatory agencies. The first of the approved clinical trials which have initiated human gene therapy aim at treating both inherited diseases (such as severe combined immunodeficiency caused by lack of adenosine deaminase in peripherial T-lymphoctes, cystic fibrosis, and familial hypercholesterolemia) as well as noninherited disease such as cancer (Wolfe J. H., Recent progress in gene therapy for inherited disease. Curr. Opinion in Pediatr. 6: 213-219, 1994; Sanda M. G. et al., Gene therapy for urologic cancer. J. Urology 44:617-624, 1994; O'Malley B. W. et al., Somatic gene therapy in otolaryngology-head and neck surgery. Arch. Otolaryngol. Head Neck Surgery 119:1191-1197, 1993; Engelhardt J. F. et al., Direct gene transfer of human CFTR into human bronchial epithelia of xenografts with Ei-deleted adenoviruses. Nature Genetics 4: 27-34, 1993; Lemarchand P. et al., Adenovirus-mediated transfer of recombinant human alpha1-antitrypsin cDNA to human endothelial cells. PNAS (USA) 89: 6482-6486, 1992; Jaffe H. A. et al., Adenovirus-mediated in vivo gene transfer and expression in normal rat liver. Nature Genetics 1:372-378, 1992).
The development of suitable, safe and effective gene transfer systems is a major goal of research in gene therapy. Thus far, viruses have been extensively used as vectors for gene therapy. For example, retroviruses have been widely used, but a major disadvantage is that they can only be used as vectors which target actively dividing cells. In addition, retroviruses do not accomodate large DNA inserts readily. Adeno-associated viruses are also limited in the ability to accomodate large inserts, yet replication defective adenovirus has been successfully used for transfer of a variety of genes into cells in culture and in vivo. Adenoviruses can accomodate larger inserts than retroviruses, but extrachromasomal expression usually only lasts for a few weeks. Herpes viruses have been exploited for specific gene transfer trials into the central nervous system. Herpes viruses can carry large foreign DNA inserts, and may remain latent for long periods of time. In spite of the availability of replication defective viruses, concerns about the safety and efficiency of such viral vectors has generated interest in the development of nonviral gene transfer systems such as liposome-DNA complexes and receptor mediated endocytosis (Felgner P. L. et al., PNAS (USA) 84: 7413-7417, 1987; Hyde Nature 362: 250-255, 1993; Nu G.Y. J. Biol. Chem. 266: 14338, 1991).
A major hurdle for effective gene therapy is the development of methods for targeting the gene transfer to appropriate target cells and tissues. Ex vivo gene transfer into explanted cultured cells and implantation of the treated cells has been used for the treatment of hematopoietic tissues (U.S. Pat. No. 5,399,346, issued Mar. 21, 1995, Anderson et al., hereby incorporated by reference). Direct injection into tissues, intravenous or intra-arterial administration, inhalation, or topical application have also been used. Major drawbacks to all of these methods are that the transduction is not highly selective, significant amounts of the therapeutic gene containing vector may be needed, and efficency of the gene transfer is severely limited by the constraints of vector concentration, time of exposure to the target, and effectiveness of the gene transfer vector.
One area of active research has been gene therapy into mammalian kidneys, but the results have been disappointing because of problems with efficiency of gene transfer (Woolf A. S. et al., Gene transfer into the mammalian kidney: First steps towards renal gene therapy. Kidney Int. 43: Suppl. 39: S116-S119, 1993). Moullier et al. (Adenoviral-mediated gene transfer to renal tubular cells in vivo. Kidney Int. 45: 1220-1225, 1994), showed some adenovirus-mediated transfer of lacZ gene into rat tubular but not glomerular cells following a combination of infusion of the virus into the renal artery and retrograde infusion into the vector. Simple infusion of soluble virus does not appear to be an efficient transfer system. Better results were obtained by Tomita et al., (Direct in vivo gene introduction into rat kidney. Biochem. Biophys. Res. Commun. 186: 129-134, 1992), who infused a complex of Sendai virus and liposomes into the rat renal artery in vivo. This resulted in expression of the marker gene in about 15% of the glomerular cells.
It would be useful to the medical arts, to be able to have apparatus and methods for the efficient administration of gene therapy to target cells and tissues which overcomes the limitations inherent to each gene transfer vector.